A new method was developed in rats to examine the permeability at the blood-brain barrier to drugs and other agents. The method takes into account cerebral blood flow. Generally, permeability is related linearly to the octanol/water partition coefficient, a measure of lipid solubility. Pharmacokinetic principles for the central nervous system were established which take into account blood-brain barrier transport, intracellular drug distribution, and drug washout by cerebrospinal fluid. The principles make it possible to calculate brain concentration of drugs from measured plasma concentration curves and peripheral loss, in acute as well as steady-state drug administration regimens. Osmotic treatment of the blood-brain barrier has been used in man for allowing anti-neoplastic agents into the brain in treatment of brain tumors. The blood-brain barrier, following osmotic treatment, closes down more rapidly to larger than smaller intravascular molecules, and this size-dependency shoud be taken into account in designing associated therapy of central nervous system diseases. In the Rhesus monkey, we examined one of the potential side-effects of the method, namely damage to the ciliary epithelium of the eye. The damage results in transient hypotony and loss of pigmented epithelial cells, but ascorbate transport by the ciliary epithelium into aqueous humor is unaffected. Metabolic and respiratory acidosis increases uptake of intravenous flourescein by the retina of the rat eye at the blood-retina barrier (retinal pigment epithelium). Uptake is not mediated by damage to the barrier, but by a pH modification of the partition coefficient of flourescein. A model was developed which interpreted the relations in man between plasma and cerebrospinal fluid concentrations of blood proteins of differing size, in terms of diffusion and ultrafiltration at the blood-brain barrier.